Role of Insulin-like Growth Factor II Receptor in Transdifferentiation of Free Silica-induced Primary Rat Lung Fibroblasts

Objective To study the role of insulin-like growth factor II receptor in free silica-induced transdifferentiation of primary rat lung fibroblasts Methods Rat lung fibroblasts and rat alveolar macrophages were cultured. A transdifferentiation model of primary rat lung fibroblasts was induced by free silica. Levels of a-SMA protein, IGF-liR protein and mRNA were measured by immunocytochemistry, Western blot and RT-PCR, respectively. Lung fibroblasts were treated with Wortmannin. Results The expression levels of a-SMA concentration and decreased after Wortmann and IGF-IIR increased with the increasing free silica n was used. Conclusion The IGF-IIR plays an important role in free silica-induced transdifferentiation of primary rat lung fibroblasts.

Spectrofluorimetric method for determination of some angiotensin II receptor antagonists

A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA’s), namely Losartan potassium (Los-K), Irbesartan (Irb), Valsartan (Val) and Candesartan cilexetil (Cand) in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI) were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefflcients (0.9982–0.9991) were obtained over the concentration range from 0.006 mg/mL to 1.7 mg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ) without interferences from the co-formulated HCTZ or the additives commonly present in tablets.

EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .

GENE EXPRESSION OF TRANSFORMING GROWTH FACTOR β_1 TYPEII RECEPTOR IN HCC AND ITS CLINICAL SIGNIFICANCE

Objective: Transforming Growth Factor-β1 (TGF-β1)plays a central role in the process of . growth suppressionof the hepatocytes, and its type II receptor (TGF-β1R II)transfers the signal of growth suppression. In this study,the gene expression of TGF-β1R II in HCC and itsclinical significance was investigated. Methods: Theexpression of TGF-β1R II mRNA in 30 cases Of HCCtissue and the surrounding liver tissue was separatelydetected using reverse transcription-PCR. Results:The positive expression rate of TGF-β1R II mRNA wassignificantly lower in HCC tissue (11/30) than that in thesurrounding liver tissue (23/30) (P<0.01). Further, theless the cancer tissue expressed TGF-β1R II mRNA, themore poorly the tumoral hepatocyte differentiated(P<0.01) and the more portal vein cancer embolusexisted (p=0.0465). Conclusion: The decreaseexpression of TGF-β1 R II mRNA by tumoral hepatocyteresults in the defect of its negative growth regulation,and this may be one of the most important reasons forits carcinogenesis and uncontrolled growth.

The Significance of Angiotensin Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Use in Sudden Cardiac Death

Objectives: To investigate the relationship between the use of angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and hyperkalemia in patients diagnosed with sudden cardiac death. Methods: We examined oral ACE inhibitor or ARB use among cardiopulmonary arrest patients brought by ambulance to our emergency room during a 5-year period from January 2012 to December 2016. The cause of death was determined to be sudden cardiac death, despite temporary return of spontaneous circulation after starting cardiopulmonary resuscitation. Subjects were dichotomized into 2 groups, those taking and those not taking an ACE inhibitor or ARB. Variables determined retrospectively included serum potassium, estimated glomerular filtration rate as an index of kidney function and time from cardiopulmonary arrest to return of spontaneous circulation. The Mann-Whitney U-test was used to compare continuous data, and the chi-square test to compare categorical data between groups. The results are expressed as the median plus range. Statistical significance was assumed at p Results: Thirty-five patients met the inclusion criteria. The mean age was 77.1 years (range, 35 - 93 years), and there were 26 males and 9 females. Eleven subjects were ACE inhibitor or ARB users, and 24 were non-users. The serum potassium level was significantly higher in users than non-users (median, 6.2 mEq/L (range, 4.5 - 10.0) vs. 5.2 mEq/L (range, 3.6 - 8.3);p = 0.001). The estimated glomerular filtration rate was significantly lower in users than non-users (median, 25.1 mL/min/1.73 m2 (range, 4.6 - 60.3) vs. 46.9 mL/min/1.73 m2 (range, 19.8 - 97.1);p = 0.009). There was no significant difference in time from cardiopulmonary arrest to return of spontaneous circulation between the 2 groups (median, 24 minutes (range, 3 - 111) vs. 29 minutes (range, 10 - 54);p = 0.355). Conclusion: It is possible that hyperkalemia induced by ACE inhibitor or ARB use is a cause of sudden cardiac death, especially in patients with chronic kidney disease.

Association of Genetic Polymorphisms of Anti-Müllerian Hormone (AMH) and Its Type II Receptor with Ovarian Hyperstimulation Syndrome

Objective To explore the association of genetic polymorphisms in the genes encoding the anti-Miillerian hormone （AMH） and its type H receptor （AMHRII） with ovarian hyperstimulation syndrome （OHSS）. Methods Using polymerase chain reaction （PCR） and DNA sequencing techniques, the exons of AMH and AMHRII were analyzed in 27 OHSS patients （OHSS group） and 22 non-OHSS patients （control group） who were applied controlled ovarian hyper- stimulation （COH）. Single nucleotide polymorphisms （SNPs） were also analyzed. Results SNPs G〉 T at position 146 of AMH exon 1 and G〉 A at position 134 of AMH exon 2 showed significant differences between the OHSS group and control group （P〈0.05）. SNP G〉 T at position 303 of AMH exon 1 showed no significant difference between the OHSS group and control group （P〉0.05）. No SNP was detected from the AMHR H exons 1 to 11 in either groups. Conclusion Genetic polymorphisms in the AMH gene may be a cause of ovarian hypersensitivity to exogenous hormone stimulation and the development of OHSS.

CHRONIC EFFECTS OF EARLY ANGIOTENSIN-CONVERTING ENZYME INHIBITOR (QUINAPRIL) OR ANGIOTENSIN II RECEPTOR BLOCKADE (LOSARTAN) ON HEMODYNAMICS AND REMODELING IN RATS AFTER EXPERIMENTAL MYOCARDIAL INFARCTION

The long-term effects of an angiotensin-converting enzyme (ACE) inhibitor on hemodynamics and remodeling

An Investigation of Postmortem Urotensin II Receptor Levels in Brain and Kidney Tissues in a Rat Model of Cardiac Ischemia

This study aimed to investigate changes in postmortem urotensin Ⅱ receptor(UTR)levels in brain and kidney tissues in a rat model of cardiac ischemia.The rats were divided into two groups:a control group and a cardiac ischemia-induced group.Cardiac ischemia was created by an intraperitoneal injection of a single lethal dose of isoproterenol(ISO;850 mg/kg).Plasma UT,blood urea nitrogen,and creatinine levels were determined 0 h postmortem.Brain and kidney UTR mRNA expression levels were determined 0,1,3,6,12,24,4&and 72 h postmortem.The histopathological appearance of brain and kidney tissues was also evaluated.Plasma UT and plasma creatinine levels were increased in the cardiac ischemia-induced group as compared with those in the control group(P<0.001).Ischemia resulted in histopathological changes in brain and cerebellum tissue.The morphological evaluation revealed Purkinje cell degeneration(P=0.037)and dark neurons(P=0.004).The UTR expression level decreased after 1 h postmortem in the brain and after 3 h postmortem in the kidneys in the cardiac ischemia-induced group as compared with that in the control group(P<0.001).The observed changes in UTR expression levels may be valuable in clinical practice in the field of forensic medicine.These changes may be used as a marker in postmortem evaluations of sudden death caused by ischemia-induced cardiac shock.

Effects of chronic peripheral pretreatment with an angiotensin II type-1 receptor blocker on apoptosis-related molecules in rats with cerebral ischemia/reperfusion injury

Chronic systemic treatment with blockers of angiotensin II type-1 （AT1） receptors inhibits ischemia-induced apoptosis and reduces ischemic neuronal damage. However, the molecular mechanisms of AT1 receptor blockers in modulating neuronal apoptosis remain poorly understood. Pretreatment with irbesartan significantly suppressed cell apoptosis at 1-7 days following cerebral ischemia/reperfusion, increased levels of brain-derived neurotrophic factor, and elevated the ratios of Bcl-2/Bax and phosphorylated cyclic adenosine monophosphate response element-binding protein （pCREB）/CREB in the ischemic cortex at 1 day after reperfusion, as well as suppressing caspase-3 activation. Cerebral ischemia increased the mRNA expression of AT1 and AT2 receptors in the ischemic cortex, whereas irbesartan blocked this increase in AT1 expression but potentiated the expression of AT2. Therefore, this AT1 receptor blocker was neuroprotective by increasing the ratios of Bcl-2/Bax and pCREB/CREB, increasing brain-derived neurotrophic factor levels, inhibiting caspase-3 activation, and modulating AT receptor expression.

Involvement of Angiotensin II Type 1 Receptor and Calcium Channel in Vascular Remodeling and Endothelial Dysfunction in Rats with Pressure Overload

Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction(TAC)rat model.TAC was induced on ten week-old male Sprague Dawley rats and these models were treated with ATIR blocker olmesartan(1 mg/kg/day)or/and calcium channel blocker(CCB)amlodipine(0.5 mgkgday)for 14 days.After the treatment,the right common carotid artery proximal to the band(RCCA-B)was collected for further assay.Results showed that olmesartan,but not amlodipine,significantly prevented TAC-induced adventitial hyperplasia.Similarly,olmesartan,but not amlodipine,significantly prevented vascular inflammation,as indicated by increased tumor necrosis factor a(TNF-a)and increased p65 phosphorylation,an indicator of nuclear factor K-light-chain-enhancer of activated B cells(NFkB)activation in RCCA-B.In contrast,both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase(eNOS)and improved endothelium-dependent vasodilation,whereas combination of olmesartan and amlodipine showed no further synergistic protective effects.These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload,whereas ATIR and subsequent calcium channel were involved in endothelial dysfunction.

Antagonism of Angiotensin II AT1 Receptor and Silencing of CD44 Gene Expression Inhibit Cardiac Fibroblast Activation via Modulating TGF-<i>β</i>1/Smad Signaling Pathway

Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not well understood. This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts were isolated from the neonatal rat hearts;the activation of fibroblasts was evaluated using the assays of cell viability and migration, and silencing of CD44 gene expression was conducted with small interfering RNA (siRNA). Results showed that Ang II significantly increases the cell proliferation and migration in a dose-dependent manner. Upon activation, the protein levels of TGF-β1, Smad2, Smad4 and collagen I were significantly increased (all p < 0.05 vs. unstimulated cells), but these changes were significantly downregulated by the AT1 receptor blocker, telmisartan (all p < 0.05 vs. Ang II activated cells). Furthermore, mRNA and protein level of CD44 were upregulated, and there was a linear correlation between CD44 and TGF-β1 as demonstrated by Pearson correlation analysis (r = 0.955, p < 0.01). Gene transfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of CD44 mRNA and protein, significantly reduced the production of collagen I. In summary, these results indicate that the proliferation, migration and collagen production from Ang II activated cardiac fibroblasts are potentially mediated by the AT1 receptor and CD44. Such a signaling mechanism could be crucial for the production of collagen and the development of tissue fibrosis in the heart.

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

IGF-I、IGF-II及其受体在肝癌和癌旁肝组织中的表达

目的 :探讨胰岛素样生长因子I、II及其受体在肝癌和癌旁肝组织中的表达及其意义。方法 :采用DNA RNA原位杂交方法检测肝癌和癌旁肝组织中IGF I、IGF II及其受体mRNA的表达。结果 :在肝癌组织中IGF I、IGF I受体、IGF II、IGF II受体mRNA的表达率分别为 4 0 .0 %、4 6.7%、66.7%和 63 .3 % ,在癌旁肝组织中IGF I、IGF I受体、IGF II、IGF II受体mRNA的表达率分别为 4 6.7%、5 3 .3 %、70 .0 %和 73 .3 % ,有 3 6.7%的肝癌和 5 0 .0 %的癌旁肝组织同时表达四种mRNA。IGF I、IGF II及其受体mRNA在分化较差的肝癌细胞、肝细胞再生结节和不典型增生肝细胞中阳性信号最强。结论 :IGF I、IGF II及其受体在肝细胞癌变过程中发挥重要作用 ,肝癌的发生发展与IGF I、IGF IR、IGF II、IGF

血管紧张素II对巨噬细胞(THP-1细胞)凝集素样氧化低密度脂蛋白受体表达的影响

目的 :研究AngII对人单核 /巨噬细胞 (THP - 1细胞 )凝集素样氧化低密度脂蛋白受体 (LOX - 1 )蛋白表达和基因转录的影响 ,从细胞蛋白、分子水平探讨AngII和巨噬细胞LOX - 1相互之间的关系 ,以进一步了解两者在动脉粥样硬化中的地位。方法 :将不同浓度AngII(1× 1 0 - 9- 1× 1 0 - 5mol/L)与经 0 1 μmol/L佛波酯 (PMA)诱导分化后的THP - 1细胞共孵育 2 4h ,以及将 1× 1 0 - 6 mol/L浓度的AngII与诱导分化后的THP - 1细胞作用不同时间0、3、6、1 2、2 4、48h后 ,用细胞酶联免疫法和半定量RT -PCR分别检测LOX - 1蛋白和mRNA表达的情况。结果 :未经诱导的THP - 1细胞不表达LOX - 1mRNA ;而经PMA诱导后 ,THP - 1细胞停止增殖 ,由单核细胞分化成为巨噬细胞 ,并表达LOX - 1mRNA。不同浓度的AngII作用诱导分化后的THP - 1细胞 2 4h,细胞LOX - 1蛋白和mRNA的表达呈浓度依赖性显著增加。同一浓度的AngII作用THP - 1细胞 ,可呈时间依赖性诱导LOX - 1蛋白和mRNA表达 ,其趋势是 3h左右开始增加 ,2 4h左右至最高峰 ,之后逐渐减低。结论 :经PMA诱导分化后的THP - 1细胞表达LOX- 1 ;AngII能明显增强分化后的THP - 1细胞表达LOX - 1蛋白和mRNA ,并呈浓度和时间依赖性。AngII这种作用可能是促进动脉粥样硬化发生、发?

大麻素Ⅱ型受体在股骨头坏死中的研究进展

大麻素Ⅱ型受体(CB2R)是内源性大麻素系统的重要组成部分,因其具有镇痛、抗炎、抗癫痫、抗纤维化及调节骨代谢等作用,已被广泛应用于临床及研究。近年来利用CB2R治疗多种疑难疾病已成为研究热点,尤其是对于骨科疾病的治疗。目前针对早中期股骨头坏死(ONFH)患者尚无疗效确切的方法,由于CB2具有抗炎、缓解疼痛、促进BMSCs成骨分化以及维持骨重塑稳态等作用,因此对其展开研究,希望CB2R能成为治疗ONFH的有效靶点。

Peroxisome proliferator-activated receptors for hypertension

Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes(α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin Ⅱ receptor blockers, should be studied.This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.

氯沙坦对血管紧张素II致培养的牛脑微血管内皮细胞损伤的保护作用

目的 观察氯沙坦对血管紧张素II(AngII)致牛脑微血管内皮细胞 (BCMECs)损伤的保护作用。方法 用分光光度计测定培养的BCMECs乳酸脱氢酶 (LDH)的漏出量 ,流式细胞仪测定BCMECs细胞间粘附分子 1(ICAM 1)的表达量 ,硝酸还原酶法和放射免疫分析法分别测定BCMECs上清液中一氧化氮 (NO)和内皮素 1(ET1 )的含量。结果 AngII呈剂量依赖性增加BCMECsLDH漏出、NO和ET1 释放及ICAM 1表达 ,氯沙坦对此均有明显抑制作用。结论 氯沙坦抑制AngII致体外培养BCMECs的损伤。

The angiotensin Ⅱ type 1 receptor and receptor-associated proteins

The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl- terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxy1-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

血管紧张素II及其受体在血管平滑肌细胞迁移中的作用

目的 :探讨血管紧张素II (AngII)及其受体 (ATRs)在局部血管损伤后血管平滑肌细胞 (VSMC)迁移中的作用及其机制。方法 :以体外培养VSMC为基础 ,采用细胞化学和改良Boyden’schamber的方法 ,观察AngⅡ干预VSMC后AngII受体的表达、VSMC迁移能力的变化、肌动蛋白纤维丝的动态组装变化 ,并探讨AT1R拮抗剂、AT2 R拮抗剂对上述观测指标的影响。结果 :AngII 10 -7mol/L可以刺激VSMC发生迁移 ,该作用是通过影响VSMC内应力纤维动态组装而实现的 ;AngII干预VSMC后可使AT1R表达上调 ,随着作用时间延长AT1R表达水平下降。AT1R拮抗剂可下调AT1R表达。AngII通过AT1R的介导发挥其影响VSMC迁移能力的生物学效应。AT2 R对此无明显影响。结论 :AngII通过AT1R介导来调节VSMC内肌动蛋白微丝的动态组装 ,进而改变VSMC的迁移能力 。